Breast Tumors in Mice Eradicated Using Cancer
VaccineFindings Could Lead To New Immune Therapy for Breast Cancer

(Philadelphia, PA) - A team from the University
of Pennsylvania School of Medicine has shown that by using a
cancer vaccine based on the bacterium Listeria monocytogenes,
they can cure mice with established breast tumors. Cancer vaccines, which
are more properly described as immunotherapy, work by boosting an immune
response against tumor-associated antigens. Using Listeria, the
researchers, led by Yvonne Paterson, PhD, Professor of
Microbiology, delivered the tumor-associated antigen HER-2/Neu to immune
cells. HER-2/Neu is overexpressed in 20 to 40 percent of all breast cancers
and also present in many cancers of the ovaries, lung, pancreas, and gastrointestinal
tract. These cells eventually enlist killer T cells to seek out and destroy
the tumor cells that display the HER-2/Neu molecule.

"We found that we can stop the tumor from growing out to 100 days,
at which time we stopped measuring since this is a long time for experiments
of this type," says Paterson. "The tumors stopped growing or
went completely away." The researchers published their findings in
the September 15 issue of the Journal of Immunology.

"The problem that we encounter is that often by the time a patient
presents with cancer, they've developed immune tolerance to the tumor
antigen, particularly when the antigen is expressed at low levels on normal
tissue as with Her2/Neu," explains Paterson. "So how is the
body to mount a strong enough immune reaction?"

In general, bacteria are good at inducing both innate and adaptive immune
responses, activating such immune cells as macrophages, dendritic cells,
and T cells. This helps jump-start the immune response to break tolerance.

But, why Listeria over other bacteria as a vehicle to deliver
a tumor-associated antigen? Because of Listeria's unusual life
style. Normally, when bacteria get taken up into an antigen-presenting
cell, they are engulfed by a phagocytic vacuole where they get killed-whereupon
their proteins get broken down into smaller pieces (peptides) and attached
to MHC Class 2 molecules. These egress to the cell surface, where they
expand and activate helper T cells, which are enlisted into the immune
response.

But Listeria has evolved to escape from this vacuole and survive
inside the cytosol of antigen-presenting cells, where it can replicate
and grow, unlike other bacteria. So, although some of the bacteria are
destroyed in the vacuole that feeds the MHC class II pathway of antigen
presentation with the induction of helper T cells, others survive by escaping
into the cytosol of the cell. This is important because the antigen-processing
pathway that feeds antigenic peptides to the surface of the cell for recognition
by killer T cells is generated in this cellular compartment. "We
reasoned that if we could get Listeria to secrete a foreign protein
into the interior of the cell, it would target that pathway and would
elicit a strong killer T cell response, and we have shown that,"
says Paterson. "Listeria is almost unique in the bacterial
kingdom in doing this."

In this model, pieces of the very large HER-2/Neu molecule are broken
up into little fragments and bound to the MHC Class 1 molecule within
the antigen-presenting cell. This is what the killer T cell "sees"
at the cell surface. These killer T cells, which are being produced in
the spleen, where Listeria usually colonizes, seek out and destroy
the tumor. This system ensures an increase in the production of killer
T cells that can recognize the HER-2/Neu pieces on the surface of the
tumor cell. In addition, the Penn team helped the immune system along
by fusing the tumor antigen to a bacterial protein that seems to activate
antigen-presenting cells. They have found that by doing this the immune
system now recognizes regions of the HER-2/neu molecule that are not immunogenic
when presented by other vaccine approaches.

Paterson first hit on the idea of using Listeria as a cancer
vaccine vector over ten years ago. "It took a while to dissect what
elements of an immune response were best able to cause the rejection of
established tumors," she says. "But in the last couple of years
it has paid off and we are very excited to see the technology finally
being tested in cancer patients. The dream of the cancer immunotherapist
is to provide an alternative and more humane way of controlling metastatic
disease than current chemotherapies."

The Listeria vector is currently being prepared for a clinical
trial targeting a tumor antigen associated with cervical cancer by Advaxis
Inc., a cancer vaccine biotech company that has licensed Penn patents
on the use of Listeria monocytogenes as a vaccine vector. Paterson
is the scientific founder of Advaxis and Chair of the Scientific Advisory
Board. The successful demonstration that the Listeria vector
technology can also be used with the HER-2/neu molecule paves the way
for applying this promising cancer vaccine approach to breast cancer.

This research was funded by the Department of Defense and the National
Cancer Institute. Co-authors are Reshma Singh and Mary E. Dominiecki,
both from Penn, as well as Elizabeth M. Jaffee from the Johns Hopkins
University School of Medicine.

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